Patel, V. et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet. 17, 1578-1590

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Human Molecular Genetics (Impact Factor: 6.39). 07/2008; 17(11):1578-90. DOI: 10.1093/hmg/ddn045
Source: PubMed


Polycystic kidney disease (PKD) is an inherited disorder that is characterized by the accumulation of cysts in the renal parenchyma and progressive decline in renal function. Recent studies suggest that PKD arises from abnormalities of the primary cilium. We have previously shown that kidney-specific inactivation of the ciliogenic gene Kif3a during embryonic development produces kidney cysts and renal failure. Here, we used tamoxifen-inducible, kidney-specific gene targeting to inactivate Kif3a in the postnatal mouse kidney. Kidney-specific inactivation of Kif3a in newborn mice resulted in the loss of primary cilia and produced kidney cysts primarily in the loops of Henle, whereas inactivation in adult mice did not lead to the rapid development of cysts despite a comparable loss of primary cilia. The age-dependence and locations of the cysts suggested that cyst formation required increased rates of cell proliferation. To test this possibility, we stimulated cell proliferation in the adult kidney by inducing acute kidney injury and tubular regeneration. Acute kidney injury induced cyst formation in adult Kif3a mutant mice. Analysis of pre-cystic tubules in Kif3a mutant mice showed that the loss of cilia did not stimulate cell proliferation but instead resulted in aberrant planar cell polarity as manifested by abnormalities in the orientation of cell division. We conclude that primary cilia are required for the maintenance of planar cell polarity in the mammalian kidney and that acute kidney injury exacerbates cystic disease.

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Available from: Vishal Patel, May 26, 2014
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    • "KAP3 has the location to associate with cargoes through small G proteins, whereas KIF3A/KIF3B bond to the MTs [23]. The homolog of KIF3 in sea urchin has been reported to be a heterotrimer composed of SpKRP85, SpKRP95 and SpKAP115 [24]–[26]. KIF3 is responsible for the formation and elongation of cilia along with the central pair of MTs [19]. OSM-3 functions in the anterograde transport of cargoes that can mediate sensory ciliary growth in sensory neurons and inner labial neurons [27]. "
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    ABSTRACT: Background Spermatogenesis represents the transformation process at the level of cellular development. KIF3A and KIF3B are believed to play some roles in the assembly and maintenance of flagella, intracellular transport of materials including organelles and proteins, and other unknown functions during this process. During spermatogenesis in Eriocheir sinensis, if the sperm shaping machinery is dependent on KIF3A and KIF3B remains unknown. Methodology/Principal Findings The cDNA of KIF3A and KIF3B were obtained by designing degenerate primers, 3′RACE, and 5′RACE. We detected the genetic presence of kif3a and kif3b in the heart, muscle, liver, gill, and testis of E. sinensis through RT-PCR. By western blot analysis, the protein presence of KIF3A and KIF3B in heart, muscle, gill, and testis reflected the content in protein level. Using in situ hybridization and immunofluorescence, we could track the dynamic location of KIF3A and KIF3B during different developmental phases of sperm. KIF3A and KIF3B were found surrounding the nucleus in early spermatids. In intermediate spermatids, these proteins expressed at high levels around the nucleus and extended to the final phase. During the nuclear shaping period, KIF3A and KIF3B reached their maximum in the late spermatids and were located around the nucleus and concentrated in the acrosome to some extent. Conclusions/Significance Our results revealed that KIF3A and KIF3B were involved in the nuclear and cellular morphogenesis at the levels of mRNA and protein. These proteins can potentially facilitate the intracellular transport of organelles, proteins, and other cargoes. The results represent the functions of KIF3A and KIF3B in the spermatogenesis of Crustacea and clarify phylogenetic relationships among the Decapoda.
    PLoS ONE 05/2014; 9(5):e97645. DOI:10.1371/journal.pone.0097645 · 3.23 Impact Factor
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    • "However, the inactivation of Pkd1 after completion of the postnatal stage of kidney development in mice (postnatal day 14) does not lead to accelerated cyst formation [38]. Analogous results were found after late inactivation of the ciliary motor protein Kif3a or IFT88 [35, 36], suggesting that quiescent cells in the adult kidney do not require cilia or PC-1 for maintaining tubular morphology in the intermediate term (the kidneys do form cysts in the long term). The second piece of evidence involves the osmo-sensor TRPV4, a transient receptor potential cation channel that forms a polymodal channel complex with PC-2 [34]. "
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    ABSTRACT: Since the discovery that proteins mutated in different forms of polycystic kidney disease (PKD) are tightly associated with primary cilia, strong efforts have been made to define the role of this organelle in the pathogenesis of cyst formation. Cilia are filiform microtubular structures, anchored in the basal body and extending from the apical membrane into the tubular lumen. Early work established that cilia act as flow sensors, eliciting calcium transients in response to bending, which involve the two proteins mutated in autosomal dominant PKD (ADPKD), polycystin-1 and -2. Loss of cilia alone is insufficient to cause cyst formation. Nevertheless, a large body of evidence links flow sensing by cilia to aspects relevant for cyst formation such as cell polarity, Stat6- and mammalian target of rapamycin signalling. This review summarizes the current literature on cilia and flow sensing with respect to PKD and discusses how these findings intercalate with different aspects of cyst formation.
    Nephrology Dialysis Transplantation 01/2013; 28(3). DOI:10.1093/ndt/gfs524 · 3.58 Impact Factor
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    • "In addition to kidney cysts, PKD patients generally also exhibit liver disease. Abnormalities in electrolyte secretion (Yamaguchi et al., 1997), EGF and cAMP dependent cell proliferation (Hanaoka and Guggino (2000); Richards et al., 1998), cell-matrix interaction (Ramasubbu et al., 1998; Wilson et al., 1992) and planar cell polarity (Fisher et al., 2006; Patel et al., 2008) have all been attributed to the disease mechanism of PKD. However, the exact cause of cystogenesis is yet unknown. "

    Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease, 03/2012; , ISBN: 978-953-51-0234-2
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